Rationale: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin–angiotensin system.

Objectives: To investigate the physiological role of (P)RR in lipid metabolism in vivo.

Methods and Results: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism. In line with our earlier report, hepatic (P)RR silencing increased plasma LDL-C (LDL cholesterol). Unexpectedly, this also resulted in markedly reduced plasma triglycerides in a SORT1-independent manner in C57BL/6 mice fed a normal- or high-fat diet. In LDLR-deficient mice, hepatic (P)RR inhibition reduced both plasma cholesterol and triglycerides, in a diet-independent manner. Mechanistically, we found that (P)RR inhibition decreased protein abundance of ACC (acetyl-CoA carboxylase) and PDH (pyruvate dehydrogenase). This alteration reprograms hepatic metabolism, leading to reduced lipid synthesis and increased fatty acid oxidation. As a result, hepatic (P)RR inhibition attenuated diet-induced obesity and hepatosteatosis.

Conclusions: Collectively, our study suggests that (P)RR plays a key role in energy homeostasis and regulation of plasma lipids by integrating hepatic glucose and lipid metabolism.

理由：血浆 LDL（低密度脂蛋白）水平升高是心血管疾病的既定风险因素。最近，我们报道了（原）肾素受体（[P]RR）通过 LDLR（LDL 受体）和 SORT1（sortilin-1）在体外调节 LDL 代谢，独立于肾素-血管紧张素系统。

目的：研究(P)RR在体内脂质代谢中的生理作用。

方法和结果：我们使用 N-乙酰半乳糖胺修饰的反义寡核苷酸特异性抑制 C57BL/6 小鼠的肝 (P)RR 表达，并研究了这对脂质代谢的影响。与我们之前的报告一致，肝脏（P）RR 沉默增加了血浆 LDL-C（LDL 胆固醇）。出乎意料的是，在喂食正常或高脂肪饮食的 C57BL/6 小鼠中，这也导致血浆甘油三酯以 SORT1 非依赖性方式显着降低。在 LDLR 缺陷小鼠中，肝脏 (P)RR 抑制以不依赖饮食的方式降低了血浆胆固醇和甘油三酯。从机制上讲，我们发现 (P)RR 抑制降低了 ACC（乙酰辅酶A羧化酶）和 PDH（丙酮酸脱氢酶）的蛋白质丰度。这种改变重新编程肝脏代谢，导致脂质合成减少和脂肪酸氧化增加。因此，

结论：总的来说，我们的研究表明 (P)RR 通过整合肝脏葡萄糖和脂质代谢在能量稳态和血浆脂质调节中起关键作用。